This is a request for renewal of an RSDA Level II Award to support an ongoing program designed to determine the role of the locus coeruleus (LC)-norepinephrine (NE) system in the adaptive response to stressors and in stress-related psychiatric disorders. This goal has been approached by investigating the neurotransmitters and circuitry underlying activation of the LC-NE system by physiological stressors and determining the functional and clinically relevant consequences of this activation. Four major advances toward this goal were made during the previous funding period: 1) The stress neurohormone, corticotropin-releasing factor (CRF) was found to be the neurotransmitter that activates the LC during hypotensive stress; 2) LC activation by neurotransmitter CRF was found to be necessary for the forebrain EEG activation produced by hypotensive stress, implying that one function of LC activation during stress is to increase or maintain arousal; 3) LC activation by stressors of different modalities was found to be mediated by different neurotransmitter systems; 4) Repeated stress, which produces an animal model of depression, was found to increase CRF function in the LC and chronic antidepressant administration to non- stressed animals was found to interfere with CRF neurotransmission in LC. These results suggested that CRF neurotransmission in the LC may be an important etiological factor in depression and a target for the actions of antidepressant treatments. The proposed research will extend these studies using state of the art anatomical and in vivo electrophysiological techniques to: 1) Further characterize CRF-immunoreactive cells and fibers in the LC region in order to understand the circuitry underlying the role of this region in stress responses; 2) Identify the neurotransmitters and circuitry involved in LC activation by different physiological challenges including, hypotension, bladder distention, hypoglycemia and colon distention; and 3) Characterize the mechanisms underlying changes in CRF neurotransmission in the LC produced by repeated stress and determine whether these changes are sensitive to antidepressant treatment.